Heterocyclic compounds as immunomodulators

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.16/781,943, filed on Feb. 4, 2020; which is a continuation of U.S.patent application Ser. No. 16/444,857, filed on Jun. 18, 2019; which isa continuation of U.S. patent application Ser. No. 16/171,478, filed onOct. 26, 2018; which is a continuation of U.S. patent application Ser.No. 15/906,765, filed on Feb. 27, 2018; which is a continuation of U.S.patent application Ser. No. 15/603,744, filed on May 24, 2017; whichclaims the benefit of U.S. Provisional Application No. 62/396,326, filedon Sep. 19, 2016; and U.S. Provisional Application No. 62/341,918, filedon May 26, 2016, each of which is incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

The present application is concerned with pharmaceutically activecompounds. The disclosure provides compounds as well as theircompositions and methods of use. The compounds modulate PD-1/PD-L1protein/protein interaction and are useful in the treatment of variousdiseases including infectious diseases and cancer.

BACKGROUND OF THE INVENTION

The immune system plays an important role in controlling and eradicatingdiseases such as cancer. However, cancer cells often develop strategiesto evade or to suppress the immune system in order to favor theirgrowth. One such mechanism is altering the expression of co-stimulatoryand co-inhibitory molecules expressed on immune cells (Postow et al, J.Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitoryimmune checkpoint, such as PD-1, has proven to be a promising andeffective treatment modality.

Programmed cell death-1 (PD-1), also known as CD279, is a cell surfacereceptor expressed on activated T cells, natural killer T cells, Bcells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005,23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201). Itfunctions as an intrinsic negative feedback system to prevent theactivation of T-cells, which in turn reduces autoimmunity and promotesself-tolerance. In addition, PD-1 is also known to play a critical rolein the suppression of antigen-specific T cell response in diseases likecancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245;Postow et al, J. Clinical Oncol 2015, 1-9).

The structure of PD-1 consists of an extracellular immunoglobulinvariable-like domain followed by a transmembrane region and anintracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). Theintracellular domain contains two phosphorylation sites located in animmunoreceptor tyrosine-based inhibitory motif and an immunoreceptortyrosine-based switch motif, which suggests that PD-1 negativelyregulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al,Nat Immunol 2001, 2, 261-268), and they differ in their expressionpatterns. PD-L1 protein is upregulated on macrophages and dendriticcells in response to lipopolysaccharide and GM-CSF treatment, and on Tcells and B cells upon T cell receptor and B cell receptor signaling.PD-L1 is also highly expressed on almost all tumor cells, and theexpression is further increased after IFN-γ treatment (Iwai et al,PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5).In fact, tumor PD-L1 expression status has been shown to be prognosticin multiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al,Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2expression, in contrast, is more restricted and is expressed mainly bydendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation ofPD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal thatinhibits IL-2 and IFN-γ production, as well as cell proliferationinduced upon T cell receptor activation (Carter et al, Eur J Immunol2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34). Themechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibitT cell receptor signaling such as Syk and Lck phosphorylation (Sharpe etal, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axisalso attenuates PKC-θ activation loop phosphorylation, which isnecessary for the activation of NF-κB and AP1 pathways, and for cytokineproduction such as IL-2, IFN-γ and TNF (Sharpe et al, Nat Immunol 2007,8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman etal, J Exp Med 2000, 192(7):1027-34).

Several lines of evidence from preclinical animal studies indicate thatPD-1 and its ligands negatively regulate immune responses.PD-1-deficient mice have been shown to develop lupus-likeglomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using anLCMV model of chronic infection, it has been shown that PD-1/PD-L1interaction inhibits activation, expansion and acquisition of effectorfunctions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439,682-7). Together, these data support the development of a therapeuticapproach to block the PD-1-mediated inhibitory signaling cascade inorder to augment or “rescue” T cell response. Accordingly, there is aneed for new compounds that block PD-1/PD-L1 protein/proteininteraction.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, and a pharmaceuticallyacceptable carrier or excipient.

The present disclosure further provides methods of modulating orinhibiting PD-1/PD-L1 protein/protein interaction, which comprisesadministering to an individual a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

DETAILED DESCRIPTION

I. Compounds

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt or stereisomer thereof, wherein:

Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered heteroaryl, or 4-to 10-membered heterocycloalkyl, each of which is optionally substitutedwith 1 to 5 independently selected R⁶ substituents;

or two adjacent R⁶ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring, a fused 5-,6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-,6- or 7-membered heterocycloalkyl ring and fused 5- or 6-memberedheteroaryl ring each have 1-4 heteroatoms as ring members selected fromN, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents;

-   -   or two R⁶ substituents attached to the same ring carbon atom of        Cy, taken together with the carbon atom to which they are        attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl ring        or a C₃₋₆ cycloalkyl ring, wherein the 4-, 5-, 6- or 7-membered        heterocycloalkyl ring and C₃₋₆ cycloalkyl ring are each        optionally substituted with 1, 2 or 3 independently selected        R^(b) substituents;

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR⁷, SR⁷, NH₂, —NHR⁷, —N(R⁷)₂,NHOR⁷, C(O)R⁷, C(O)NR⁷R⁷, C(O)OR⁷, OC(O)R⁷, OC(O)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(O)OR⁷, NR⁷C(O)NR⁷R⁷, C(═NR⁷)R⁷, C(═NR⁷)NR⁷R⁷, NR⁷C(═NR⁷)NR⁷R⁷,NR⁷S(O)R⁷, NR⁷S(O)₂R⁷, NR⁷S(O)₂NR⁷R⁷, S(O)R⁷, S(O)NR⁷R⁷, S(O)₂R⁷, andS(O)₂NR⁷R⁷, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹ are each optionallysubstituted with 1, 2 or 3 R^(b) substituents;

each R⁷ is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁷ are each optionally substituted with1, 2 or 3 R^(b) substituents;

-   -   each R² is independently selected from H, C₁₋₆ alkyl, C₃₋₁₀        cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀ aryl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, C₂₋₆ alkenyl, C₂₋₆        alkynyl, halo, CN, OH, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₁₋₆        haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄alkyl)₂, NHOR⁸, C(O)R⁸,        C(O)NR⁸R⁸, C(O)OR⁸, OC(O)R⁸, OC(O)NR⁸R⁸, NR⁸C(O)R⁸, NR⁸C(O)OR⁸,        NR⁸C(O)NR⁸R⁸, C(═NR⁸)R⁸, C(═NR⁸)NR⁸R⁸, NR⁸C(═NR⁸)NR⁸R⁸,        NR⁸S(O)R⁸, NR⁸S(O)₂R⁸, NR⁸S(O)₂NR⁸R⁸, S(O)R⁸, S(O)NR⁸R⁸,        S(O)₂R⁸, and S(O)₂NR⁸R⁸, wherein each R⁸ is independently        selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄        alkoxy, C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀        aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 5-10 membered heteroaryl, 4-10        membered heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄        alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,        wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,        C₃₋₁₀ cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀ aryl,        C₆₋₁₀ aryl-C₁₋₄ alkyl-, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and        (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R² and R⁸ are        each optionally substituted with 1, 2 or 3 independently        selected R^(d) substituents;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵ and R⁶ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents;

or two R³ substituents attached to the same carbon atom, taken togetherwith the carbon atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl ring or a C₃₋₆ cycloalkyl ring, wherein the4-, 5-, 6- or 7-membered heterocycloalkyl ring and C₃₋₆ cycloalkyl ringare each optionally substituted with 1, 2 or 3 independently selectedR^(q) substituents;

or R⁴ and R⁵ together with the nitrogen atom to which they are attached,form a 4-, 5-, 6-, 7-membered heterocycloalkyl having 0 to 2 additionalheteroatoms as ring members selected from N, O and S, wherein one or tworing atoms of the heterocycloalkyl are optionally oxidized to formC(═O), NO, S(═O) or SO₂ and the heterocycloalkyl is optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

-   -   each R^(a) is independently selected from H, CN, C₁₋₆ alkyl,        C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally        substituted with 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents;

-   -   each R^(e) is independently selected from H, CN, C₁₋₆ alkyl,        C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R^(e) are each optionally        substituted with 1, 2 or 3 independently selected R^(f)        substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o),C(O)NR^(o)R^(o), C(O)OR), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o),NR^(o)R^(o)), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₄ haloalkyl of R^(n)are each optionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 R^(p) substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r), OR^(r),SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) are each optionally substitutedwith 1, 2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR'S(O)₂R^(i), NR'S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), wherein theC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl,5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each optionally substitutedby 1, 2, or 3 R^(i) substituents independently selected from C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, NHOR^(k), OR^(k), SR^(k), C(O)R^(k),C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k),NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k),C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k),S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k),and S(O)₂NR^(k)R^(k), wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, 5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy of R^(i) areeach optionally substituted with 1, 2 or 3 independently selected R^(q)substituents;

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

each R^(i) or R^(k) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(i) or R^(k) are each optionallysubstituted with 1-3 independently selected R^(p) substituents;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(o) or R^(r) is independently selected from H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6 memberedheterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl,wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl of R^(o) or R^(r) are each optionally substituted with 1, 2 or 3R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁹, NR⁹R⁹and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl,4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) areeach optionally substituted with halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl,5-6 membered heteroaryl and 4-6 membered heterocycloalkyl and each R⁹ isindependently C₁₋₆ alkyl;

the subscript n is an integer of 1, 2 or 3; and

the subscript m is an integer of 1, 2, 3, 4, 5 or 6.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or a stereoisomer, wherein:

Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered heteroaryl, or 4-to 10-membered heterocycloalkyl, each of which is optionally substitutedwith 1 to 5 independently selected R⁶ substituents;

or two adjacent R⁶ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring, a fused 5-,6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-,6- or 7-membered heterocycloalkyl ring and fused 5- or 6-memberedheteroaryl ring each have 1-4 heteroatoms as ring members selected fromN, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(h) substituents;

or two R⁶ substituents attached to the same ring carbon atom of Cy,taken together with the carbon atom to which they are attached, form a4-, 5-, 6- or 7-membered heterocycloalkyl ring or a C₃₋₆ cycloalkylring, wherein the 4-, 5-, 6- or 7-membered heterocycloalkyl ring andC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents;

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR⁷, SR⁷, NH₂, —NHR⁷, —N(R⁷)₂,NHOR⁷, C(O)R⁷, C(O)NR⁷R⁷, C(O)OR⁷, OC(O)R⁷, OC(O)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(O)OR⁷, NR⁷C(O)NR⁷R⁷, C(═NR⁷)R⁷, C(═NR⁷)NR⁷R⁷, NR⁷C(═NR⁷)NR⁷R⁷,NR⁷S(O)R⁷, NR⁷S(O)₂R⁷, NR⁷S(O)₂NR⁷R⁷, S(O)R⁷, S(O)NR⁷R⁷, S(O)₂R⁷, andS(O)₂NR⁷R⁷, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹ are each optionallysubstituted with 1, 2 or 3 R^(b) substituents;

each R⁷ is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁷ are each optionally substituted with1, 2 or 3 R^(b) substituents;

each R² is independently selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, NHOR⁸, C(O)R⁸,C(O)NR⁸R⁸, C(O)OR⁸, OC(O)R⁸, OC(O)NR⁸R⁸, NR⁸C(O)R⁸, NR⁸C(O)OR⁸,NR⁸C(O)NR⁸R⁸, C(═NR⁸)R⁸, C(═NR⁸)NR⁸R⁸, NR⁸C(═NR⁸)NR⁸R⁸, NR⁸S(O)R⁸,NR⁸S(O)₂R⁸, NR⁸S(O)₂NR⁸R⁸, S(O)R⁸, S(O)NR⁸R⁸, S(O)₂R⁸, and S(O)₂NR⁸R⁸,wherein each R⁸ is independently selected from H and C₁₋₄ alkyloptionally substituted with 1 or 2 groups independently selected fromhalo, OH, CN and C₁₋₆ alkoxy; and wherein the C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ alkoxy of R² are eachoptionally substituted with 1 or 2 substituents independently selectedfrom halo, OH, CN and C₁₋₄ alkoxy;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a),

S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), and S(O)₂NR^(a)R^(a), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R³, R⁴, R⁵ and R⁶ are each optionally substituted with 1, 2,3, or 4 R^(b) substituents;

or two R³ substituents attached to the same carbon atom, taken togetherwith the carbon atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl ring or a C₃₋₆ cycloalkyl ring, wherein the4-, 5-, 6- or 7-membered heterocycloalkyl ring and C₃₋₆ cycloalkyl ringare each optionally substituted with 1, 2 or 3 independently selectedR^(q) substituents;

or R⁴ and R⁵ together with the nitrogen atom to which they are attached,form a 4-, 5-, 6-, 7-membered heterocycloalkyl having 0 to 2 additionalheteroatoms as ring members selected from N, O and S, wherein one or tworing atoms of the heterocycloalkyl are optionally oxidized to formC(═O), NO, S(═O) or SO₂ and the heterocycloalkyl is optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(e) are each optionally substitutedwith 1, 2 or 3 independently selected R^(g) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 independently selected R^(p)substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each optionallysubstituted by 1, 2, or 3 R^(i) substituents independently selected fromC₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

-   -   or any two R^(g) substituents together with the nitrogen atom to        which they are attached form a 4-, 5-, 6-, or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, or 3        independently selected R^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(i), R^(k), R^(o) or R^(p) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆-10 aryl, 5 or 6-membered heteroaryl, C₁₋₄haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl of R^(i), R^(k), R^(o) or R^(p) are each optionallysubstituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁹, NR⁹R⁹and C₁₋₄haloalkoxy, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are eachoptionally substituted with halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl and4-6 membered heterocycloalkyl and each R⁹ is independently C₁₋₆ alkyl;

the subscript n is an integer of 1, 2 or 3; and

the subscript m is an integer of 1, 2, 3, 4, 5 or 6.

In some embodiments of compounds of Formula (I), Cy is C₆₋₁₀ aryl,optionally substituted with 1 to 5 independently selected R⁶substituents. In certain embodiments, Cy is phenyl or naphthyl, each ofwhich is optionally substituted with 1 to 4 independently selected R⁶substituents. In certain embodiments, Cy is phenyl optionallysubstituted with 1 to 5 independently selected R⁶ substituents. Incertain embodiments, Cy is phenyl. In certain embodiments, Cy is2,3-dihydro-1,4-benzodioxin-6-yl, optionally substituted with 1 to 5independently selected R⁶ substituents.

In some embodiments of compounds of Formula (I), Cy is C₃₋₁₀ cycloalkyl,optionally substituted with 1 to 5 independently selected R⁶substituents. In certain embodiments, Cy is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, eachof which is optionally substituted with 1 to 5 independently selected R⁶substituents.

In some embodiments of compounds of Formula (I), Cy is 5- to 14-memberedheteroaryl, optionally substituted with 1 to 5 independently selected R⁶substituents. In certain embodiments, Cy is pyridy, primidinyl,pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, azolyl,oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl,isoquinolinyl, naphthyridinyl, indolyl, benzothiophenyl, benzofuranyl,benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl or1,3,4-oxadiazolyl, each of which is optionally substituted with 1 to 5independently selected R⁶ substituents. In certain embodiments, Cy isthiophenyl or pyridyl, each of which is optionally substituted with 1 to5 independently selected R⁶ substituents. In some embodiments, Cy is2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each ofwhich is optionally substituted with 1 to 5 independently selected R⁶substituents.

In some embodiments of compounds of Formula (I), Cy is 4- to 10-memberedheterocycloalkyl, optionally substituted with 1 to 5 independentlyselected R⁶ substituents. In certain embodiments, Cy is azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl,2,3-dihydro-1,4-benzodioxin-6-yl, or thiomorpholino, each of which isoptionally substituted with 1 to 4 independently selected R⁶substituents. In some embodiments, Cy is 3,6-dihydro-2H-pyran-4-yl,optionally substituted with 1 to 5 independently selected R⁶substituents.

In some embodiments of compounds of Formula (I), Cy is phenyl, 5- or6-membered heteroaryl, C₃₋₆ cycloalkyl or 5- or 6-memberedheterocycloalkyl, each of which is optionally substituted with 1 to 5independently selected R⁶ substituents. In certain instances, Cy isphenyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₃₋₆ cycloalkyl or 3,6-dihydro-2H-pyran-4-yl, each of which isoptionally substituted with 1 to 5 R⁶ substituents.

In some embodiments, Cy is phenyl, cyclohexyl, thiophenyl,3,6-dihydro-2H-pyran-4-yl, pyridyl, 1H-indazolyl or 1-cyclohexenyl, eachof which is optionally substituted with 1, 2 or 3 R⁶ substituents.

In some embodiments, Cy is phenyl, cyclohexyl, or 1-cyclohexenyl, eachof which is optionally substituted with 1, 2 or 3 R⁶ substituents.

In some embodiments, Cy is phenyl optionally substituted with 1, 2 or 3R⁶ substituents. For example, Cy is unsubstituted phenyl.

In some embodiments, Cy is cyclohexyl optionally substituted with 1, 2or 3 R⁶ substituents. For example, Cy is unsubstituted cyclohexyl.

In some embodiments, Cy is 1-cyclohexenyl optionally substituted with 1,2 or 3 R⁶ substituents. For example, Cy is unsubstituted 1-cyclohexenyl.

In some embodiments, a compound provided herein is a compound havingFormula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein the subscript p is an integer of 1, 2, 3, 4 or 5; R¹, R², R³,R⁴, R⁵, R⁶, m, n, and p are as defined herein.

In some embodiments, a compound provided herein is a compound havingFormula (III):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein the subscript p is an integer of 1, 2, 3, 4 or 5; R¹, R², R³,R⁴, R⁵, R⁶, m, n, and p are as defined herein.

In some embodiments, a compound provided herein is a compound havingFormula (IV):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein the subscript p is an integer of 1, 2, 3, 4 or 5; R¹, R², R³,R⁴, R⁵, R⁶, m, n, and p are as defined herein.

In some embodiments, a compound provided herein is a compound havingFormula (V):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein the subscript p is an integer of 1, 2, 3, 4 or 5; R¹, R², R³,R⁴, R⁵, R⁶, m, n, and p are as defined herein.

In some embodiments, R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN, NO₂, OR⁷, NH₂, —NHR⁷, —N(R⁷)₂,NHOR⁷, C(O)R⁷, C(O)NR⁷R⁷, C(O)OR⁷, OC(O)R⁷, OC(O)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(O)OR⁷, NR⁷S(O)R⁷, NR⁷S(O)₂R⁷, NR⁷S(O)₂NR⁷R⁷, S(O)R⁷, S(O)NR⁷R⁷,S(O)₂R⁷, and S(O)₂NR⁷R⁷, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy of R¹ are each optionallysubstituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, or CN, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy of R¹ areeach optionally substituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R¹ is halo, C₁₋₆ alkyl, or CN. For example, R¹ isCH₃, CN or Cl. In some embodiments, R¹ is CH₃ or CN. In someembodiments, R¹ is CH₃. In other embodiments, R¹ is CN.

In some embodiments, R² is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, and —N(C₁₋₄ alkyl)₂, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ alkoxy of R² are eachoptionally substituted with 1 or 2 substituents independently selectedfrom halo, OH, CN and C₁₋₄ alkoxy.

In some embodiments, R² is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OH, C₁₋₆ alkoxy, and C₁₋₆haloalkyl. In some instances, R² is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl. In some embodiments, R² isindependently selected from H and C₁₋₆ alkyl. For example, R² is H.

In some embodiments, R³ is independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN,and OR^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R³are each optionally substituted with 1, 2, 3, or 4 R^(b) substituents.

In some embodiments, R³ is independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl. In some instances, R³ is H orC₁₋₆ alkyl. For example, R³ is H.

In some embodiments, R⁴ is independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN,and OR^(a), wherein the C₁₋₆ alkyl,

C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R³ are each optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents.

In some embodiments, R⁴ is independently selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl. In some instances, R⁴ is H or C₁₋₆alkyl.

In some embodiments, R⁵ is C₁₋₆ alkyl, phenyl, phenyl-C₁₋₄ alkyl, C₃₋₁₀cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, 4-10 membered heterocycloalkyl,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl, 5-6 membered heteroaryl or(5-6 membered heteroaryl)-C₁₋₄ alkyl-, each of which is optionallysubstituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R⁵ is C₁₋₆ alkyl optionally substituted with 1, 2or 3 R^(b) substituents. In some embodiments, R⁵ is phenyl optionallysubstituted with 1, 2 or 3 R^(b) substituents. In some embodiments, R⁵is C₃₋₁₀ cycloalkyl optionally substituted with 1, 2 or 3 R^(b)substituents. In some embodiments, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-optionally substituted with 1, 2 or 3 R^(b) substituents. In someembodiments, R⁵ is 4-10 membered heterocycloalkyl optionally substitutedwith 1, 2 or 3 R^(b) substituents. In some embodiments, R⁵ is (4-10membered heterocycloalkyl)-C₁₋₄ alkyl optionally substituted with 1, 2or 3 R^(b) substituents. In some embodiments, R⁵ is 5-6 memberedheteroaryl optionally substituted with 1, 2 or 3 R^(b) substituents. Insome embodiments, R⁵ is (5-6 membered heteroaryl)-C₁₋₄ alkyl- optionallysubstituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R⁵ is cyclobutyl, cyclopropyl, methyl,cyclopropylmethyl, 1H-pyrazol-4-ylethyl, 2,2-dimethylpropyl,tetrahydro-2H-pyran-4-yl, spiro[3.3]heptan-2-yl,tetrahydro-2H-pyran-4-yl, cyclohexyl, tetrahydro-2H-pyran-3-yl,cyclopentyl, cyclohexylmethyl, butyl,4,5,6,7-tetrahydro-1H-indazol-5-yl, tetrahydrofuran-3-yl, or propyl,each of which is optionally substituted with 1, 2 or 3 R^(b)substituents.

In some embodiments, R⁴ and R⁵ taken together form 4-, 5- or 6-memberedheterocycloalkyl having 0-1 additional heteroatom as ring member,wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3R^(b) substituents.

In some embodiments, R⁴ and R⁵ taken together form pyrrolidin-1-yl,1-piperidinyl, 1-piperazinyl or morpholinyl, each of which is optionallysubstituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R⁴ and R⁵ taken together form pyrrolidin-1-yl,which is optionally substituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R⁵ is 3-hydroxycyclobutyl, cyclopropyl, methyl,1-(hydroxymethyl)cyclopropylmethyl, 1-methyl-1H-pyrazol-4-ylethyl,3-hydroxy-2,2-dimethylpropyl, 3-(hydroxymethyl)cyclobutyl,spiro[3.3]heptan-2-yl, tetrahydro-2H-pyran-4-yl,2-(hydroxymethyl)cyclohexyl, 3-methoxycyclobutyl,tetrahydro-2H-pyran-3-yl, 2-(hydroxymethyl)cyclopentyl,2-hydroxycyclohexylmethyl, cyclohexyl, 1-methylcyclopropyl,4-hydroxycyclohexyl, methylcyclopropylmethanol,1-(4-isopropylpiperazin-1-ypethanone, cyclopentylmethanol, 2-butan-1-ol,4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid,cyclohex-4-ylacetonitrile, cyclohex-4-ylcarbonitrile,cyclohex-4-ylcarboxylic acid, tetrahydrofuran-3-yl,1-methoxypropan-2-yl, cyclobut-3-ylcarboxylic acid, or1-(4-chlorophenyl)cyclohexane-1-carboxylic acid.

In some embodiments, R⁴ and R⁵ taken together form3-(hydroxymethyl)-4-methylpyrrolidin-1-yl,2-hydroxyethylpyrrolidin-1-yl, 3-(1-hydroxyethyl)pyrrolidin-1-yl,3-(hydroxymethyl)pyrrolidin-1-yl, or pyrrolidin-1-yl.

In some embodiments, R⁴ is H and R⁵ is C₁₋₆ alkyl, phenyl, phenyl-C₁₋₄alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, 4-10 memberedheterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl, 5-6membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₄ alkyl-, each ofwhich is optionally substituted with 1, 2 or 3 R^(b) substituents.

In some embodiments, R⁴ is H and R⁵ is cyclobutyl, cyclopropyl, methyl,cyclopropylmethyl, 1H-pyrazol-4-ylethyl, 2,2-dimethylpropyl,tetrahydro-2H-pyran-4-yl, spiro[3.3]heptan-2-yl,tetrahydro-2H-pyran-4-yl, cyclohexyl, tetrahydro-2H-pyran-3-yl,cyclopentyl, cyclohexylmethyl, butyl,4,5,6,7-tetrahydro-1H-indazol-5-yl, tetrahydrofuran-3-yl, or propyl,each of which is optionally substituted with 1, 2 or 3 R^(b)substituents.

In some embodiments, R⁴ is H and R⁵ is 3-hydroxycyclobutyl, cyclopropyl,methyl, 1-(hydroxymethyl)cyclopropylmethyl,1-methyl-1H-pyrazol-4-ylethyl, 3-hydroxy-2,2-dimethylpropyl,3-(hydroxymethyl)cyclobutyl, spiro[3.3]heptan-2-yl,tetrahydro-2H-pyran-4-yl, 2-(hydroxymethyl)cyclohexyl,3-methoxycyclobutyl, tetrahydro-2H-pyran-3-yl,2-(hydroxymethyl)cyclopentyl, 2-hydroxycyclohexylmethyl, cyclohexyl,1-methylcyclopropyl, 4-hydroxycyclohexyl, methylcyclopropylmethanol,1-(4-isopropylpiperazin-1-yl)ethanone, cyclopentylmethanol,2-butan-1-ol, 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid,cyclohex-4-ylacetonitrile, cyclohex-4-ylcarbonitrile,cyclohex-4-ylcarboxylic acid, tetrahydrofuran-3-yl,1-methoxypropan-2-yl, cyclobut-3-ylcarboxylic acid, or1-(4-chlorophenyl)cyclohexane-1-carboxylic acid.

In some embodiments, R^(b) is independently selected from halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, CN, OH, NH₂, OR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), andOC(O)NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄haloalkoxy, and C₆₋₁₀ aryl of R^(b) are each optionally substitutedwith 1, 2, or 3 independently selected R^(d) substituents. In someinstances, R^(b) is independently selected from halo, C₁₋₆ alkyl, C₆₋₁₀aryl, CN, OH, NH₂, OR^(c), and C(O)NR^(c)R^(c), C(O)OR^(c); wherein theC₁₋₄ alkyl and C₆₋₁₀ aryl of R^(b) are each optionally substituted with1, 2, or 3 independently selected R^(d) substituents.

In some embodiments, R^(d) is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, CN, NH₂, and OR^(c), wherein the C₁₋₄ alkyl ofR^(d) are each optionally substituted with 1, 2 or 3 independentlyselected R^(f) substituents. In some instances, R^(d) is independentlyselected from halo, CN, and OR^(e).

In some embodiments, R^(c) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(c) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(f) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, and CN. Insome instances, R^(c) is independently selected from H and C₁₋₆ alkyl.

In some embodiments, R⁶ is independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN,and OR^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R³are each optionally substituted with 1, 2, 3, or 4 R^(b) substituents.

In some embodiments, R⁶ is H, halo, C₁₋₆ alkyl or C₁₋₆ alkoxy. In someinstances, R⁶ is H. In other instances, R⁶ is C₁₋₆ alkoxy. For example,R⁶ is methoxy.

In some embodiments, the subscript m is 1 or 2.

In some embodiments, R², R³ and R⁶ are each H.

In some embodiments, provided herein is a compound of any one of theformula provided herein (e.g., Formula I), or a pharmaceuticallyacceptable salt, wherein:

Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered heteroaryl, or 4-to 10-membered heterocycloalkyl, each of which is optionally substitutedwith 1 to 5 independently selected R⁶ substituents;

or two adjacent R⁶ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring, a fused 5-,6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-,6- or 7-membered heterocycloalkyl ring and fused 5- or 6-memberedheteroaryl ring each have 1-4 heteroatoms as ring members selected fromN, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents;

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, CN, NO₂, OR⁷, NH₂, —NHR⁷, —N(R⁷)₂, NHOR⁷, C(O)R⁷, C(O)NR⁷R⁷,C(O)OR⁷, OC(O)R⁷, OC(O)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(O)OR⁷, NR⁷S(O)R⁷,NR⁷S(O)₂R⁷, NR⁷S(O)₂NR⁷R⁷, S(O)R⁷, S(O)NR⁷R⁷, S(O)₂R⁷, and S(O)₂NR⁷R⁷,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, andC₁₋₆ haloalkoxy of R¹ are each optionally substituted with 1, 2 or 3R^(b) substituents;

each R⁷ is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁷ are each optionally substituted with1, 2 or 3 R^(b) substituents;

each R² is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, CN, OH, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, NH₂,—NH—C₁₋₄ alkyl, and —N(C₁₋₄ alkyl)₂, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ alkoxy of R² are each optionallysubstituted with 1 or 2 substituents independently selected from halo,OH, CN and C₁₋₄ alkoxy;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵ and R⁶ areeach optionally substituted with 1, 2, 3, or 4 R^(b) substituents;

or R⁴ and R⁵ together with the nitrogen atom to which they are attached,form a 4-, 5-, 6-, 7-membered heterocycloalkyl having 0 to 2 additionalheteroatoms as ring members selected from N, O and S, wherein one or tworing atoms of the heterocycloalkyl are optionally oxidized to formC(═O), NO, S(═O) or SO₂ and the heterocycloalkyl is optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl of R^(a) are each optionally substituted with1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, NH₂, NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e),C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e),NR^(e)C(O)R^(e), NR^(e)C(O)OR^(e), S(O)R^(e), S(O)NR^(e)R^(e),S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), andS(O)₂NR^(e)R^(e), wherein the C₁₋₄ alkyl of R^(d) are each optionallysubstituted with 1, 2 or 3 independently selected R^(f) substituents;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(e) are each optionally substitutedwith 1, 2 or 3 independently selected R^(g) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of W are each optionally substituted with 1, 2, 3, 4,or 5 R^(f) substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)OR^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R^(f)are each optionally substituted with 1, 2, 3, 4, or 5 R¹¹ substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo and CN;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of R^(g) are each optionally substituted with 1-3independently selected R^(p) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, and CN, wherein the C₁₋₆ alkyl ofR^(h) are each optionally substituted by 1, 2, or 3 substituentsindependently selected from C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄alkyl, and C₁₋₄ haloalkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(p) is independently selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl of R^(p) are each optionally substituted with 1, 2 or 3R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₄ haloalkoxy;

the subscript n is an integer of 1, 2 or 3; and

the subscript m is an integer of 1, 2, 3, 4, 5 or 6.

In some embodiments, provided herein is a compound of any one of theformula provided herein (e.g., Formula I), or a pharmaceuticallyacceptable salt, wherein:

Cy is C₆₋₁₀ aryl or C₃₋₆ cycloalkyl, each of which is optionallysubstituted with 1 to 5 independently selected R⁶ substituents;

or two adjacent R⁶ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring or a fused5-, 6- or 7-membered heterocycloalkyl ring, wherein the fused 5-, 6- or7-membered heterocycloalkyl ring has 1-4 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring and fused 5-,6- or 7-membered heterocycloalkyl ring are each optionally substitutedwith 1, 2 or 3 independently selected R^(b) substituents;

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, or CN, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy of R¹ are each optionallysubstituted with 1, 2 or 3 R^(b) substituents;

each R² is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, CN, OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, and OR^(a), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵ and R⁶are each optionally substituted with 1, 2, 3, or 4 R^(h) substituents;

or R⁴ and R⁵ together with the nitrogen atom to which they are attached,form a 4-, 5-, 6-, 7-membered heterocycloalkyl having 0 to 2 additionalheteroatoms as ring members selected from N, O and S, wherein one or tworing atoms of the heterocycloalkyl are optionally oxidized to formC(═O), NO, S(═O) or SO₂ and the heterocycloalkyl is optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylof R^(a) are each optionally substituted with 1, 2, 3, 4, or 5 R^(d)substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, NH₂, and OR^(e);

each W is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of R^(e) are each optionally substituted with 1, 2 or 3independently selected R^(g) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, CN, OH, NH₂, OR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), andOC(O)NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, and C₆₋₁₀ aryl of R^(h) are each optionally substituted with1, 2, or 3 independently selected R^(d) substituents; each R^(c) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

the subscript n is an integer of 1 or 2; and

the subscript m is an integer of 1, 2, or 3.

In some embodiments, provided herein is a compound of any one of theformula provided herein (e.g., Formula I), or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein:

Cy is C₆₋₁₀ aryl, 5-14 membered heteroaryl, 5-10 memberedheterocycloalkyl or C₃₋₆ cycloalkyl, each of which is optionallysubstituted with 1 to 5 independently selected R⁶ substituents;

or two adjacent R⁶ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring or a fused5-, 6- or 7-membered heterocycloalkyl ring, wherein the fused 5-, 6- or7-membered heterocycloalkyl ring has 1-4 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring and fused 5-,6- or 7-membered heterocycloalkyl ring are each optionally substitutedwith 1, 2 or 3 independently selected R^(b) substituents;

R¹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, or CN, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy of R¹ are each optionallysubstituted with 1, 2 or 3 R^(b) substituents;

each R² is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, CN, OH, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, and OR^(a), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵ and R⁶are each optionally substituted with 1, 2, 3, or 4 R^(b) substituents;

or two R³ substituents attached to the same carbon atom, taken togetherwith the carbon atom to which they are attached, form a 4-, 5-, 6- or7-membered heterocycloalkyl ring or a C₃₋₆ cycloalkyl ring, wherein the4-, 5-, 6- or 7-membered heterocycloalkyl ring and

C₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents;

or R⁴ and R⁵ together with the nitrogen atom to which they are attached,form a 4-, 5-, 6-, 7-membered heterocycloalkyl having 0 to 2 additionalheteroatoms as ring members selected from N, O and S, wherein one or tworing atoms of the heterocycloalkyl are optionally oxidized to formC(═O), NO, S(═O) or SO₂ and the heterocycloalkyl is optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

each R^(a) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,or C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylof R^(a) are each optionally substituted with 1, 2, 3, 4, or 5 R^(d)substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, CN, NH₂, and OR^(e);

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl of R^(e) are each optionally substituted with1, 2 or 3 independently selected R^(g) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, CN, OH, NH₂, OR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), andOC(O)NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, and C₆₋₁₀ aryl of R^(b) are each optionally substituted with1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl;

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₄ haloalkoxy;

the subscript n is an integer of 1 or 2; and

the subscript m is an integer of 1, 2, or 3.

In some embodiments, provided herein is a compound of any one of theformula provided herein (e.g., Formula I), or a pharmaceuticallyacceptable salt, wherein:

Cy is C₆₋₁₀ aryl or C₃₋₆ cycloalkyl, each of which is optionallysubstituted with 1 to 5 independently selected R⁶ substituents;

or two adjacent R⁶ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused 5-, 6- or 7-memberedheterocycloalkyl ring, wherein the fused 5-, 6- or 7-memberedheterocycloalkyl ring has 1-4 heteroatoms as ring members selected fromN, O and S and wherein a fused 5-, 6- or 7-membered heterocycloalkylring is optionally substituted with 1, 2 or 3 independently selectedR^(h) substituents;

R¹ is halo, C₁₋₆ alkyl, or CN;

each R² is independently selected from H and C₁₋₆ alkyl;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, and OR^(a), wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵ and R⁶are each optionally substituted with 1, 2, 3, or 4 R^(b) substituents;

or R⁴ and R⁵ together with the nitrogen atom to which they are attached,form a 4-, 5-, 6-, 7-membered heterocycloalkyl having 0 to 2 additionalheteroatoms as ring members selected from N, O and S, wherein theheterocycloalkyl is optionally substituted with 1, 2 or 3 independentlyselected R^(b) substituents;

each R^(a) is independently selected from H or C₁₋₆ alkyl;

each R^(d) is independently selected from C₁₋₆ alkyl, halo, CN, andOR^(e);

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

each R^(b) substituent is independently selected from halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, CN, OH, NH₂, OR^(c),C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c), andOC(O)NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, and C₆₋₁₀ aryl of R^(h) are each optionally substituted with1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl;

each R^(h) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

the subscript n is an integer of 1; and

the subscript m is an integer of 1.

In some embodiments, provided herein is a compound of any one of theformula provided herein (e.g., Formula I), or a pharmaceuticallyacceptable salt, wherein:

Cy is C₆₋₁₀ aryl or C₃₋₆ cycloalkyl, each of which is optionallysubstituted with 1 to 5 independently selected R⁶ substituents;

or two adjacent R⁶ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused 5-, 6- or 7-memberedheterocycloalkyl ring, wherein the fused 5-, 6- or 7-memberedheterocycloalkyl ring has 1-4 heteroatoms as ring members selected fromN, O and S and wherein a fused 5-, 6- or 7-membered heterocycloalkylring is optionally substituted with 1, 2 or 3 independently selectedR^(h) substituents;

R¹ is halo, C₁₋₆ alkyl, or CN;

each R² is H;

R³, R⁴, R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, and OR^(a), wherein the C₁₋₆ alkyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵ and R⁶ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents;

or R⁴ and R⁵ together with the nitrogen atom to which they are attached,form a 4-, 5-, 6-, 7-membered heterocycloalkyl having 0 to 2 additionalheteroatoms as ring members selected from N, O and S, wherein theheterocycloalkyl is optionally substituted with 1, 2 or 3 independentlyselected R^(b) substituents;

each R^(a) is independently selected from H or C₁₋₆ alkyl;

each R^(d) is independently selected from halo, CN, and OR^(e);

each R^(e) is independently selected from H and C₁₋₆ alkyl;

each R^(h) substituent is independently selected from halo, C₁₋₆ alkyl,C₆₋₁₀ aryl, CN, OH, OR^(c), C(O)NR^(c)R^(c), and C(O)OR^(c); wherein theC₁₋₄ alkyl and C₆₋₁₀ aryl of R^(h) are each optionally substituted with1, 2, or 3 independently selected R^(d) substituents;

each R^(c) is independently selected from H and C₁₋₆ alkyl;

each R^(h) is C₁₋₆ alkyl;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1 R^(h) substituent;

the subscript n is an integer of 1; and

the subscript m is an integer of 1.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)-includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “Cn-m alkenyl” refers to an alkenylgroup having n to m carbons. In some embodiments, the alkenyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groupsinclude, but are not limited to, ethenyl, n-propenyl, isopropenyl,n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula which alsomay be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, indazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine),indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl fusedderivatives of cyclopentane, cyclohexane and the like. An example ofsuch cycloalkyl is 4,5,6,7-tetrahydro-1H-indazolyl. A cycloalkyl groupcontaining a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,spiro[3.3]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, andthe like. In some embodiments, the cycloalkyl group is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10ring members, 4-7 ring members, or 4-6 ring members. Included within theterm “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfido group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl fused derivatives of piperidine, morpholine, azepine,etc. A heterocycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Examples of heterocycloalkyl groups includeazetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl,dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, andthiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as(3-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in Schemes 1-4.

Compounds of formula 1-7 can be synthesized using procedures as outlinedin Scheme 1. Selective coupling of aromatic halides of formula 1-1(e.g., Hal¹ and Hal² is Cl, Br or I) with compounds of formula 1-2[wherein M is a boronic acid, boronic ester or an appropriatelysubstituted metal (e.g., M is B(OH)₂, Sn(Bu)₃, or ZnBr)] to givecompound 1-3 can be achieved under suitable Suzuki conditions {e.g., inthe presence of a palladium catalyst, such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) and a bicarbonate or carbonate base}, orsuitable Stille conditions [e.g., in the presence of a palladiumcatalyst, such as, but not limited to, Pd(dba)₂] or suitable Negishiconditions [e.g., in the presence of a palladium catalyst, such as, butnot limited to, tetrakis(triphenylphosphine)palladium(O)]. Compound 1-5can be obtained from compound 1-3 and 4-oxopiperdine derivatives 1-4using Buchwald-Hartwig amination under standard conditions {e.g., in thepresence of a palladium catalyst, such as, but not limited to,(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladiumand a base, such as, but not limited to, cesium carbonate or sodiumtert-butoxide}. Reductive amination of compound 1-5 with amine 1-6 canafford compound 1-7.

Alternatively, compounds of formula 2-5 can be synthesized as shown inScheme 2. Selective Buchwald-Hartwig coupling of the aromatic halide 2-1with 4-aminopiperidine derivatives 2-2 can give compounds of formula2-3. Installation of Cy ring can be achieved using similar conditions asdescribed in Scheme 1 by coupling of aryl halide 2-3 with compound 2-4to give compounds of formula 2-5.

Compounds of formula 3-5 can be synthesized using an alternativeprocedure shown in Scheme 3. Compound 3-3 can be prepared by thetreatment of compound 3-1 (Hal is C₁, Br or I) and an appropriatepiperdine derivative 3-2 with a strong base, such as, but not limitedto, NaH or Cs₂CO₃ in DMSO or DMF. Similarly, ring Cy can be introducedvia coupling of aromatic halides 3-3 with compound 3-4 under conditionsas descried in Scheme 1 to give compound 3-5.

Compounds of formula 4-5 can also be prepared using procedures outlinedin Scheme 4. The starting material of formula 4-1 can be synthesizedusing similar conditions as descried in Scheme 1. Selective coupling ofthe aromatic halide 4-1 with 4-aminopiperidine derivatives of formula4-2 under suitable Buckwald-Hartwig amination conditions can givecompounds of formula 4-3. Removal of Boc protecting group can give4-aminopiperdine derivative 4-4, followed by alkylation or reductiveamination can afford the final products of formula 4-5.

III. Uses of the Compounds

Compounds of the present disclosure can inhibit the activity ofPD-1/PD-L1 protein/protein interaction and, thus, are useful in treatingdiseases and disorders associated with activity of PD-1 and the diseasesand disorders associated with PD-L1 including its interaction with otherproteins such as PD-1 and B7-1 (CD80). In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in canceror chronic infection, including enhancement of response to vaccination.In some embodiments, the present disclosure provides a method forinhibiting or blocking the PD-1/PD-L1 protein/protein interaction. Themethod includes administering to an individual or a patient a compoundof Formula (I) or any of the formulas as described herein or of acompound as recited in any of the claims and described herein, or apharmaceutically acceptable salt or a stereoisomer thereof. Thecompounds of the present disclosure can be used alone, in combinationwith other agents or therapies or as an adjuvant or neoadjuvant for thetreatment of diseases or disorders, including cancer or infectiondiseases. For the uses described herein, any of the compounds of thedisclosure, including any of the embodiments thereof, may be used.

The compounds of the present disclosure inhibit the PD-1/PD-L1protein/protein interaction, resulting in a PD-1 pathway blockade. Theblockade of PD-1 can enhance the immune response to cancerous cells andinfectious diseases in mammals, including humans. In some embodiments,the present disclosure provides treatment of an individual or a patientin vivo using a compound of Formula (I) or a salt or stereoisomerthereof such that growth of cancerous tumors is inhibited. A compound ofFormula (I) or of any of the formulas as described herein, or a compoundas recited in any of the claims and described herein, or a salt orstereoisomer thereof, can be used to inhibit the growth of canceroustumors. Alternatively, a compound of Formula (I) or of any of theformulas as described herein, or a compound as recited in any of theclaims and described herein, or a salt or stereoisomer thereof, can beused in conjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells in an individualor a patient. The method includes administering to the individual orpatient in need thereof a therapeutically effective amount of a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

In some embodiments, the present disclosure provides a method ofenhancing, stimulating and/or increasing the immune response in apatient. The method includes administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof.

Examples of cancers that are treatable using the compounds orcombinations of the present disclosure include, but are not limited to,ewing sarcoma, cholangiocarcinoma, bone cancer, pancreatic cancer, skincancer, cancer of the head or neck, cutaneous or intraocular malignantmelanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of theanal region, stomach cancer, testicular cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,endometrial cancer, carcinoma of the cervix, carcinoma of the vagina,carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, chronic or acute leukemias includingacute myeloid leukemia, chronic myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, solid tumors of childhood,lymphocytic lymphoma, cancer of the bladder, cancer of the kidney orurethra, carcinoma of the renal pelvis, neoplasm of the central nervoussystem (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axistumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma,epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers, especiallymetastatic cancers that express PD-L1.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer andlung cancer (e.g. non-small cell lung cancer and small cell lungcancer). Additionally, the disclosure includes refractory or recurrentmalignancies whose growth may be inhibited using the compounds of thedisclosure.

In some embodiments, cancers that are treatable using the compounds orcombinations of the present disclosure include, but are not limited to,solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer,endometrial cancer, ovarian cancer, uterine cancer, renal cancer,hepatic cancer, pancreatic cancer, gastric cancer, breast cancer,triple-negative breast cancer, lung cancer, cancers of the head andneck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.),hematological cancers (e.g., lymphoma, leukemia such as acutelymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chroniclymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL,mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

PD-1 pathway blockade with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria, fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,a salt thereof. Examples of viruses causing infections treatable bymethods of the present disclosure include, but are not limit to, humanimmunodeficiency virus, human papillomavirus, influenza, hepatitis A, B,C or D viruses, adenovirus, poxvirus, herpes simplex viruses, humancytomegalovirus, severe acute respiratory syndrome virus, ebola virus,and measles virus. In some embodiments, viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus,flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus,respiratory syncytial virus, mumpsvirus, rotavirus, measles virus,rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus,papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus andarboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic bacteria causing infections treatable by methodsof the disclosure include chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria,salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Non-limiting examples ofpathogenic fungi causing infections treatable by methods of thedisclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic parasites causing infections treatable by methodsof the disclosure include Entamoeba histolytica, Balantidium coli,Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp.,Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosomabrucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, andNippostrongylus brasiliensis.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer or infections. Examples of cancers includesolid tumors and liquid tumors, such as blood cancers. Examples ofinfections include viral infections, bacterial infections, fungusinfections or parasite infections. For example, the compounds of thepresent disclosure can be combined with one or more inhibitors of thefollowing kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR,PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFaR, PDGFpR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/F1t2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer or infections. Non-limiting examples ofinhibitors that can be combined with the compounds of the presentdisclosure for treatment of cancer and infections include an FGFRinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat andNLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor, a PI3K-gamma inhibitor such asPI3K-gamma selective inhibitor (e.g., INCB50797), a Pim inhibitor, aCSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Ax1, and Mer),an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK,PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1and PD-L2. In some embodiments, the immune checkpoint molecule is astimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from MR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor and the like. The compoundscan be administered in combination with one or more anti-cancer drugs,such as a chemotherapeutics. Example chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab), 4-1BB, antibodies to PD-1 and PD-L1, orantibodies to cytokines (IL-10, TGF-β, etc.). Examples of antibodies toPD-1 and/or PD-L1 that can be combined with compounds of the presentdisclosure for the treatment of cancer or infections such as viral,bacteria, fungus and parasite infections include, but are not limitedto, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirits, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel KOOLV™) Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tert, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to labeledcompounds of the invention (radio-labeled, fluorescent-labeled, etc.)that would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1protein in tissue samples, including human, and for identifying PD-L1ligands by inhibition binding of a labeled compound. Accordingly, thepresent invention includes PD-1/PD-L1 binding assays that contain suchlabeled compounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). It is to be understood that a “radio-labeled” is acompound that has incorporated at least one isotope that is radioactive(e.g., radionuclide). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro PD-L1 protein labeling and competition assays,compounds that incorporate ³H ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or willgenerally be most useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful. Insome embodiments the radionuclide is selected from the group consistingof ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. Synthetic methods for incorporatingradio-isotopes into organic compounds are known in the art.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a PD-L1 protein bymonitoring its concentration variation when contacting with the PD-L1protein, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a PD-L1 protein (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the PD-L1 protein directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of PD-L1 including its interaction with other proteins suchas PD-1 and B7-1 (CD80), such as cancer or infections, which include oneor more containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of PD-1/PD-L1 protein/protein interaction according to atleast one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

Example 12-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-{4-[(cis-3-hydroxycyclobutyl)amino]piperidin-1-yl}benzonitrile

Step 1: 2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile

A slurry of 2-bromo-6-iodobenzonitrile (1.15 g, 3.73 mmol),2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (0.706 g, 3.92 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (200 mg, 0.2 mmol) and potassium carbonate(1.5 g, 11 mmol) in 1,4-dioxane (20 mL)/water (10 mL) was degassed andrecharged with nitrogen three times. The resulting mixture was stirredat 80° C. overnight. The reaction was quenched with water, and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated under reducedpressure to afford the crude product, which is used in the next stepwithout further purification. LC-MS calculated for C₁₅H₁₁BrNO₂ [M+H]⁺m/z: 316.0; found: 315.9.

Step 2:2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-oxopiperidin-1-yl)benzonitrile

To a stirred slurry of crude2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (Step 1: 1.18g, 3.73 mmol), palladium acetate (84 mg, 0.37 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (230 mg, 0.37 mmol),and cesium carbonate (3.6 g, 11 mmol) in 1,4-dioxane (35 mL) was addedpiperidin-4-one hydrochloride (0.66 g, 4.8 mmol). The resulting mixturewas stirred at 100° C. overnight. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate, filtered and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel, eluting with 0-50% EtOAc/hexanes, to give the desiredproduct (0.46 g). LC-MS calculated for C₂₀H₁₉N₂O₃ [M+H]⁺ m/z: 335.1;found: 335.1.

Step 3:2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-{4-[(cis-3-hydroxycyclobutyl)amino]piperidin-1-yl}benzonitrile

To a stirred solution of2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4-oxopiperidin-1-yl)benzonitrile(10 mg, 0.04 mmol) in N,N-dimethylformamide (1.0 mL) were addedcis-3-aminocyclobutanol hydrochloride (6.8 mg, 0.055 mmol) and aceticacid (6.2 μL, 0.11 mmol) at room temperature. After 5 minutes, sodiumcyanoborohydride (6.9 mg, 0.11 mmol) was added. The reaction mixture wasstirred at room temperature overnight. The volatiles were removed andthe residue was purified on prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as its TFA salt. LC-MS calculated forC₂₄H₂₈N₃O₃ [M+H]⁺ m/z: 406.2; found: 406.2.

TABLE 1 The compounds in Table 1 were prepared in accordance with thesynthetic protocols set forth in Scheme 1 and Example 1, using theappropriate starting materials. LC-MS (M + H) Example Name Structure + 22-(4- (cyclopropylamino)piperidin- 1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)benzonitrile

376.2 3 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(dimethylamino)piperidin- 1-yl)benzonitrile

364.2 4 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-((l-(hydroxymethyl)cyclopropyl) methylamino)piperidin-1- yl)benzonitrile

420.2 5 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(2-(1-methyl-1H-pyrazol-4- yl)ethylamino)piperidin-1- yl)benzonitrile

444.3 6 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(3-hydroxy-2,2-dimethylpropylamino)piperidin- 1-yl)benzonitrile

422.3 7 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(tetrahydro-2H-pyran-4-ylamino)piperidin- 1-yl)benzonitrile

420.3 8 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(cis-3-(hydroxymethyl)cyclobutyl- amino)piperidin-l- yl)benzonitrile

420.2 9 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(trans-3-(hydroxymethyl)-4- methylpyrrolidin-1- yl)piperidin-1- yl)benzonitrile

434.2 10 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(spiro[3.3]heptan-2- ylamino)piperidin-l- yl)benzonitrile

430.2 11 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-((4-(4-methoxyphenyl)tetrahydro- 2H-pyran-4- yl)methylamino)piperidin-1-yl)benzonitrile

540.3 12 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(trans-2-(hydroxymethyl)cyclohexyl amino)piperidin-1- yl)benzonitrile

448.3 13 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(trans-3-methoxycyclobutylamino) piperidin-1-yl)benzonitrile

420.2 14 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(cis-3-methoxycyclobutylamino) piperidin-1-yl)benzonitrile

420.2 15 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(3-(2-hydroxyethyl)pyrrolidin-1- yl)piperidin-1- yl)benzonitrile

434.2 16 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(tetrahydro-2H-pyran-3-ylamino)piperidin- 1-yl)benzonitrile

420.2 17 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(cis-2-(hydroxymethyl)cyclopentyl amino)piperidin-l- yl)benzonitrile

434.3 18 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(trans-3-hydroxycyclobutylamino) piperidin-1-yl)benzonitrile

406.2 19 2-(2,3-dihydro-1,4- benzodioxin-6-yl)-6-[4- ({[cis-2-hydroxycyclohexyl]methyl} amino)piperidin-1- yl]benzonitrile

448.3 20 2-(4- (cyclohexylamino)piperidin- 1-yl)-6-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)benzonitrile

418.3 21 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(3-(1-hydroxyethyl)pyrrolidin-1- yl)piperidin-1- yl)benzonitrile

434.3 22 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(1-methylcyclopropylamino) piperidin-1-yl)benzonitrile

390.2 23 2-(2,3- dihvdrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(trans-3-(hydroxymethyl)cyclobutyl- amino)piperidin-1- yl)benzonitrile

420.2 24 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(trans-4-hydroxycyclohexylamino) piperidin-1-yl)benzonitrile

434.3 25 2-(2,3- dihydrobenzo[b][1,4]dioxin- 6-yl)-6-(4-(3-(hydroxymethyl)pyrrolidin- 1-yl)piperidin-1- yl)benzonitrile

420.2

Example 26(1-((1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)methyl)cyclopropyl)methanol

Step 1: 3-bromo-2-methylbiphenyl

A mixture of 1,3-dibromo-2-methylbenzene (6.0 g, 24 mmol), phenylboronicacid (2.9 g, 24 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (817 mg, 1.0 mmol) and potassium carbonate(10 g, 72 mmol) in 1,4-dioxane (100 mL) and water (70 mL) was stirred atroom temperature overnight. The reaction was quenched with water, andextracted with ethyl acetate (3×150 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel, eluting with 0-5% EtOAc/hexanes, to give the desired product(4.7 g).

Step 2: 8-(2-methylbiphenyl-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane

A stirred mixture of 1,4-dioxa-8-azaspiro[4.5]decane (0.58 g, 4.0 mmol),3-bromo-2-methylbiphenyl (0.50 g, 2.023 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium(154 mg, 0.199 mmol), sodium tert-butoxide (382 mg, 3.97 mmol) in1,4-dioxane (10 mL) was heated at 120° C. for 5 hours. The reaction wasquenched with water, and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel, eluting with 0-65%EtOAc/hexanes, to give the desired product (0.44 g). LC-MS calculatedfor C₂₄H₂₄NO₂ [M+H]⁺ m/z: 310.2; found: 310.2

Step 3: 1-(2-methylbiphenyl-3-yl)piperidin-4-one

A solution of 8-(2-methylbiphenyl-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane(0.44 g, 1.4 mmol) in tetrahydrofuran (3.0 mL)/3.0 M hydrogen chloridein water (3.0 mL) was stirred at 60° C. overnight. The reaction wasquenched with saturated aqueous NaHCO₃ and was extracted with DCM (2×30mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel, eluting with 0-25%EtOAc/hexanes, to give the desired product (0.30 g). LC-MS calculatedfor C₁₈H₂₀NO [M+H]⁺ m/z: 266.2; found: 266.1.

Step 4:(1-((1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)methyl)cyclopropyl)methanol

To a stirred solution of 1-(2-methylbiphenyl-3-yl)piperidin-4-one (10mg, 0.04 mmol) in N,N-dimethylformamide (1.0 mL),[1-(aminomethyl)cyclopropyl]methanol (5.6 mg, 0.055 mmol) and aceticacid (6.2 pt, 0.11 mmol) were added sequentially at room temperature.After 5 minutes, sodium cyanoborohydride (6.9 mg, 0.11 mmol) was added.The resulting mixture was stirred at room temperature overnight. Thevolatiles were removed under reduced pressure and the residue waspurified on prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as its TFA salt. LC-MS calculated for C₂₃H311\120 [M+H]⁺ m/z:351.2; found: 351.3.

TABLE 2 The compounds in Table 2 were prepared in accordance with thesynthetic protocols set forth in Scheme 1 and Example 26, using theappropriate starting materials. LC-MS (M + H) Example Name Structure +27 1-(4-isopropylpiperazin-1- yl)-2-(1-(2-methylbiphenyl-3-yl)piperidin-4- ylamino)ethanone

435.3 28 trans-3-(1-(2- methylbiphenyl-3- yl)piperidin-4-ylamino)cyclobutanol

337.2 29 cis-3-(1-(2-methylbiphenyl- 3-yl)piperidin-4-ylamino)cyclobutanol

337.2 30 trans-4-(1-(2- methylbiphenyl-3- yl)piperidin-4-ylamino)cyclohexanol

365.2 31 N-(2-(1-methyl-1H-pyrazol- 4-yl)ethyl)-1-(2- methylbiphenyl-3-yl)piperidin-4-amine

375.3 32 1-(2-methylbiphenyl-3-yl)- 4-(pyrrolidin-1- yl)piperidine

321.2 33 cis-4-(1-(2-methylbiphenyl- 3-yl)piperidin-4-ylamino)cyclohexanol

365.2 34 (cis-2-(1-(2- methylbiphenyl-3- yl)piperidin-4-ylamino)cyclopentyl) methanol

365.3 35 (R)-2-(1-(2-methylbiphenyl- 3-yl)piperidin-4-ylamino)butan-l-ol

339.3 36 N-cyclopropyl-1-(2- methylbiphenyl-3- yl)piperidin-4-amine

307.2

Example 37 N-cyclopentyl-1-(2-methylbiphenyl-3-yl)piperidin-4-amine

Step 1: 1-(2-methylbiphenyl-3-yl)piperidin-4-amine

A stirred mixture of tert-butyl piperidin-4-ylcarbamate (0.89 g, 4.4mmol), 3-bromo-2-methylbiphenyl (Example 26, Step 1: 1.0 g, 4.0464mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium(309 mg, 0.397 mmol), sodium tert-butoxide (764 mg, 7.95 mmol) in1,4-dioxane (11 mL) was heated at 120° C. for 5 hours. The reaction wasquenched with water, and extracted with DCM (3×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel, eluting with 0-80% EtOAc/hexanes, to givethe desired product (0.51 g). LCMS calculated for C₁₈H₂₃N₂ [M+H]⁺ m/z:267.2; Found: 267.2.

Step 2: N-cyclopentyl-1-(2-methylbiphenyl-3-yl)piperidin-4-amine

To a stirred solution of 1-(2-methylbiphenyl-3-yl)piperidin-4-amine (5mg, 0.02 mmol) in DCM (1.0 mL), acetic acid (10.7 μL, 0.188 mmol) andcyclopentanone (3.2 mg, 0.038 mmol) were added sequentially at roomtemperature. After 0.5 hours, sodium cyanoborohydride (3.6 mg, 0.056mmol) was added. After another 5 hours, the volatiles were removed underreduced pressure. The residue was purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₂₃H₃₁N₂ [M+H]⁺ m/z: 335.2; found: 335.2.

TABLE 3 The compounds in Table 3 were prepared in accordance with thesynthetic protocols set forth in Scheme 4 and Example 37, using theappropriate starting materials. LC-MS (M + H) Example Name Structure +38 1-methyl-5-(1-(2- methylbiphenyl-3- yl)piperidin-4-ylamino)-4,5,6,7-tetrahydro-1H- indazole-3-carboxylic acid

445.3 Racemic 39 2-(4-(1-(2-methylbiphenyl- 3-yl)piperidin-4-ylamino)cyclohexyl) acetonitrile

388.3 Mixture of cis- and trans-isomer 40 (Peak 1)4-(1-(2-methylbiphenyl-3- yl)piperidin-4- ylamino)cyclohexane-carbonitrile

374.2 Peak 1, t_(r) = 2.08 min 40 (Peak 2) 4-(1-(2-methylbiphenyl-3-yl)piperidin-4- ylamino)cyclohexane carbonitrile

374.2 Peak 2, t_(r) = 2.13 min 41 (Peak 1) 4-(1-(2-methylbiphenyl-3-yl)piperidin-4- ylamino)cyclohexane- carboxylic acid

393.2 Peak 1, t_(r) = 2.05 min 41 (Peak 2) 4-(1-(2-methylbiphenyl-3-yl)piperidin-4- ylamino)cyclohexane- carboxylic acid

393.2 Peak 2, t_(r) = 2.10 min 42 1-(2-methylbiphenyl-3-yl)-N-(tetrahydrofuran-3- yl)piperidin-4-amine

337.2 Racemic 43 (3-(1-(2-methylbiphenyl-3- yl)piperidin-4-ylamino)cyclobutyl) methanol

351.2 Mixture of cis- and trans-isomer 44 N-(1-methoxypropan-2-yl)-1-(2-methylbiphenyl-3- yl)piperidin-4-amine

339.2 Racemic 45 3-(1-(2-methylbiphenyl-3- yl)piperidin-4-ylamino)cyclobutane- carboxylic acid

365.2 Mixture of cis- and trans-isomer 46 (Peak 1)3-(1-(2-methylbiphenyl-3- yl)piperidin-4- ylamino)cyclohexane carboxylicacid

393.2 Peak 1, t_(r) = 2.09 min 46 (Peak 2) 3-(1-(2-methylbiphenyl-3-yl)piperidin-4- ylamino)cyclohexane carboxylic acid

393.2 Peak 2, t_(r) = 2.15 min 47 (Peak 1) 1-(4-chlorophenyl)-4-(1-(2-methylbiphenyl-3- yl)piperidin-4- ylamino)cyclohexane carboxylic acid

503.2 Peak 1, t_(r) = 2.39 min 47 (Peak 2) 1-(4-chlorophenyl)-4-(1-(2-methylbiphenyl-3- yl)piperidin-4- ylamino)cyclohexane- carboxylicacid

503.2 Peak 2, t_(r) = 2.57 min

Example 483′-methoxy-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)biphenyl-2-carbonitrile

Step 1: 2-bromo-6-(4-pyrrolidin-1-ylpiperidin-1-yl)benzonitrile

To a stirred solution of 2-bromo-6-fluorobenzonitrile (0.65 g, 3.2 mmol)and 4-pyrrolidin-1-ylpiperidine (0.500 g, 3.24 mmol) in dimethylsulfoxide (13 mL), sodium hydride (60% w/w in mineral oil, 0.259 g, 6.48mmol) was added at room temperature. The resulting mixture was heated at100° C. for 15 minutes. The reaction was cooled to room temperature,diluted with EtOAc, and washed with water. The organic layer was driedover Na₂SO₄, filtered, and the filtrate was concentrated to drynessunder reduced pressure. The residue was purified by chromatography onsilica gel, eluting with 0-65% EtOAc/DCM, to give the desired product(0.5 g). LC-MS calculated for C₁₆H₂₁BrN₃ [M+H]⁺ m/z: 334.1; found:334.1.

Step 2:3′-methoxy-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)biphenyl-2-carbonitrile

A stirred solution of 3-methoxyphenylboronic acid (0.0027 g, 0.018mmol), 2-bromo-6-(4-pyrrolidin-1-ylpiperidin-1-yl)benzonitrile (0.005 g,0.02 mmol), sodium carbonate (3.61 mg, 0.0340 mmol), and[1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (1.2mg, 0.0015 mmol) in tert-butyl alcohol (0.6 mL)/water (0.6 mL) washeated at 90° C. for 0.5 hour. The reaction mixture was cooled to roomtemperature, diluted with MeOH and purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₂₃H₂₈N₃O [M+H]⁺ m/z: 362.2; found: 362.2.

TABLE 4 The compounds in Table 4 were prepared in accordance with thesynthetic protocols set forth in Scheme 3 and Example 48 using theappropriate starting materials. LC-MS (M + H) Example Name Structure +49 3′-fluoro-3-(4-(pyrrolidin- 1-yl)piperidin-1-yl)biphenyl-2-carbonitrile

350.2 50 2-cyclohexenyl-6-(4- (pyrrolidin-1-yl)piperidin-1-yl)benzonitrile

336.2

Example 512-cyclohexyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzonitrile

A slurry of2-cyclohex-1-en-1-yl-6-(4-pyrrolidin-1-ylpiperidin-1-yl)benzonitrile(Example 50: 5 mg, 0.01 mmol) and Pd/C (10% w/w, 1.6 mg, 0.0015 mmol) inmethanol (1.0 mL) was stirred under the atmosphere of H₂ at roomtemperature. After 15 minutes, the reaction mixture was filtered and thefiltrate was purified on prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as its TFA salt. LC-MS calculated for C₂₂H₃₂N₃[M+H]⁺ m/z: 338.3; found: 338.2.

Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)Binding Assay

The assays were conducted in a standard black 384-well polystyrene platewith a final volume of 20 μL. Inhibitors were first serially diluted inDMSO and then added to the plate wells before the addition of otherreaction components. The final concentration of DMSO in the assay was1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4)with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein(19-238) with a His-tag at the C-terminus was purchased fromAcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) withFc tag at the C-terminus was also purchased from AcroBiosystems(PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay bufferand 10 pt was added to the plate well. Plates were centrifuged andproteins were preincubated with inhibitors for 40 minutes. Theincubation was followed by the addition of 10 μL of HTRF detectionbuffer supplemented with Europium cryptate-labeled anti-human IgG(PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated toSureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H). Aftercentrifugation, the plate was incubated at 25° C. for 60 min. beforereading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Finalconcentrations in the assay were −3 nM PD1, 10 nM PD-L1, 1 nM europiumanti-human IgG and 20 nM anti-His-Allophycocyanin. IC₅₀ determinationwas performed by fitting the curve of percent control activity versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Compounds of the present disclosure, as exemplified in Examples 1-51,showed ICso values in the following ranges: +=IC₅₀≤100 nM; ++=100nM<IC₅₀≤500 nM; +++=500 nM<IC₅₀≤10000 nM

Data obtained for the Example compounds using the PD-1/PD-L1 homogenoustime-resolved fluorescence (HTRF) binding assay described in Example Ais provided in Table 1.

TABLE 1 PD-1/PD-L1 HTRF Example IC₅₀ (nM) 1 + 2 + 3 ++ 4 + 5 + 6 + 7 +8 + 9 + 10 + 11 + 12 + 13 + 14 + 15 + 16 + 17 + 18 + 19 + 20 + 21 + 22 +23 + 24 + 25 + 26 + 27 ++ 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 +37 + 38 + 39 + 40 (peak 1) + 40 (peak 2) + 41 (peak 1) + 41 (peak 2) +42 + 43 + 44 + 45 + 46 (peak 1) + 46 (peak 2) + 47 (peak 1) + 47 (peak2) + 48 ++ 49 + 50 + 51 ++

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A compound of Formula (II), (III), (IV), or (V):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R¹ is halo, C₁₋₆ alkyl, or CN; each R² is H; R³ is H or C₁₋₆ alkyl; R⁴,R⁵ and R⁶ are each independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁴, R⁵ and R⁶ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents; or R⁴ and R⁵ togetherwith the nitrogen atom to which they are attached, form a 4-, 5-, 6-,7-membered heterocycloalkyl having 0 to 2 additional heteroatoms as ringmembers selected from N, O and S, wherein one or two ring atoms of theheterocycloalkyl are optionally oxidized to form C(═O), NO, S(═O) or SO₂and the heterocycloalkyl is optionally substituted with 1, 2 or 3independently selected R^(b) substituents; each R^(a) is independentlyselected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NRR^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e),NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), wherein the C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-of R^(d) are each optionally substitutedwith 1, 2 or 3 independently selected R^(f) substituents; each R^(e) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(e) areeach optionally substituted with 1, 2 or 3 independently selected R^(f)substituents; each R^(b) substituent is independently selected fromhalo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, OH, NH₂, NO₂, NHOR^(c), OR^(c), SRc, C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each optionallysubstituted with 1, 2, or 3 independently selected R^(d) substituents;each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituents;each R^(f) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(g), OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g),C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g),NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g),C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g),S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g),and S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are eachoptionally substituted with 1, 2, 3, 4, or 5 R^(n) substituents; eachR^(n) is independently selected from C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl, halo, CN,NHOR^(o), OR^(o), SR^(o), C(O)R^(o), C(O)NR^(o)R^(o), C(O)oR^(o),OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o),NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o),)C(═NR^(o)NR^(o)R^(o),)NR^(o)C(═NR^(o)NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o), wherein the C₁₋₄ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl and C₁₋₄ haloalkyl of R^(n) are each optionally substituted with1, 2 or 3 R^(q) substituents; each R^(g) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionallysubstituted with 1-3 R^(p) substituents; each R^(p) is independentlyselected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r), OR^(r),SR^(r), C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r),OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r),NR^(r)C(O)R^(r),NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NOH)NR^(r)R^(r),NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r), S(O)NR^(r)R^(r), S(O)₂R^(r),NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r) and S(O)₂NR^(r)R^(r), whereinthe C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(p) are each optionally substitutedwith 1, 2 or 3 R^(q) substituents; or any two R^(a) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionallysubstituted with 1, 2 or 3 R^(h) substituents independently selectedfrom C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, 5-6 membered heteroaryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i),C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i),NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each optionally substituted by 1, 2, or 3 R^(j) substituents;each is R^(j) independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₆ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄haloalkoxy of are each optionally substitutedwith 1, 2 or 3 independently selected R^(q) substituents; or two R^(h)groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S; eachR^(i) or R^(k) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(i) or R^(k) are each optionallysubstituted with 1-3 independently selected R^(p) substituents; or anytwo R^(c) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents; or any two R^(e) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(g) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any twoR^(o)substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents; each R^(o) or R^(r) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-6membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl of R^(o) or R^(r) are each optionally substituted with 1, 2or 3 R^(q) substituents; each R^(q) is independently selected from OH,CN, —COOH, NH₂, halo, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 memberedheterocycloalkyl, C₃₋₆ cycloalkyl, NHR⁹, NR⁹R⁹ and C₁₋₄ haloalkoxy,wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are eachoptionally substituted with halo, OH, CN, —COOH, NH₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl, 5-6membered heteroaryl and 4-6 membered heterocycloalkyl and each R⁹ isindependently C₁₋₆ alkyl; the subscript n is an integer of 1, 2 or 3;the subscript m is an integer of 1, 2, 3, 4, 5 or 6; and the subscript pis an integer or 1, 2, 3, 4 or
 5. 2. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R¹is CH₃, CN or Cl.
 3. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, R⁴ is independently selectedfrom H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, CN, and OR^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl of R⁴ are each optionally substituted with 1, 2, 3, or4 R^(b) substituents.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R⁴ is H or C₁₋₆alkyl.
 5. The compound of claim 1, or a pharmaceutically acceptable saltor a stereoisomer thereof, wherein R⁵ is C₁₋₆ alkyl, phenyl, phenyl-C₁₋₄alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, 4-10 memberedheterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl, 5-6membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₄ alkyl-, each ofwhich is optionally substituted with 1, 2 or 3 R^(b) substituents. 6.The compound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R⁵ is cyclobutyl, cyclopropyl, methyl,cyclopropylmethyl, 1H-pyrazol-4-ylethyl, 2,2-dimethylpropyl,tetrahydro-2H-pyran-4-yl, spiro[3.3]heptan-2-yl,tetrahydro-2H-pyran-4-yl, cyclohexyl, tetrahydro-2H-pyran-3-yl,cyclopentyl, cyclohexylmethyl, butyl,4,5,6,7-tetrahydro-1H-indazol-5-yl, tetrahydrofuran-3-yl, or propyl,each of which is optionally substituted with 1, 2 or 3 R^(b)substituents.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R⁵ is3-hydroxycyclobutyl, cyclopropyl, methyl,1-(hydroxymethyl)cyclopropylmethyl, 1-methyl-1H-pyrazol-4-ylethyl,3-hydroxy-2,2-dimethylpropyl, 3-(hydroxymethyl)cyclobutyl,spiro[3.3]heptan-2-yl, tetrahydro-2H-pyran-4-yl,2-(hydroxymethyl)cyclohexyl, 3-methoxycyclobutyl,tetrahydro-2H-pyran-3-yl, 2-(hydroxymethyl)cyclopentyl,2-hydroxycyclohexylmethyl, cyclohexyl, 1-methylcyclopropyl,4-hydroxycyclohexyl, methylcyclopropylmethanol,1-(4-isopropylpiperazin-1-yl)ethanone, cyclopentylmethanol,2-butan-1-ol, 4,5,6, 7-tetrahydro-1H-indazole-3-carboxylic acid,cyclohex-4-ylacetonitrile, cyclohex-4-ylcarbonitrile,cyclohex-4-ylcarboxylic acid, tetrahydrofuran-3-yl,1-methoxypropan-2-yl, cyclobut-3-ylcarboxylic acid, or1-(4-chlorophenyl)cyclohexane-1-carboxylic acid.
 8. The compound ofclaim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein R⁴ and R⁵ taken together form 4-, 5- or 6-memberedheterocycloalkyl having 0-1 additional heteroatom as ring member,wherein the heterocycloalkyl is optionally substituted with 1, 2 or 3R^(b) substituents.
 9. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R⁴ and R⁵ takentogether form pyrrolidin-1-yl, 1-piperidinyl, 1-piperazinyl ormorpholinyl, each of which is optionally substituted with 1, 2 or 3R^(b) substituents.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R⁴ and R⁵ takentogether form 3-(hydroxymethyl)-4-methylpyrrolidin-1-yl,2-hydroxyethylpyrrolidin- 1-yl, 3-(1-hydroxyethyl)pyrrolidin-1-yl,3-(hydroxymethyl)pyrrolidin- 1-yl, or pyrrolidin-1-yl.
 11. The compoundof claim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein R⁴ is H and R⁵ is C₁₋₆ alkyl, phenyl, phenyl-C₁₋₄alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, 4-10 memberedheterocycloalkyl, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl, 5-6membered heteroaryl or (5-6 membered heteroaryl)-C₁₋₄ alkyl-, each ofwhich is optionally substituted with 1, 2 or 3 R^(b) substituents. 12.The compound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R⁴ is H and R⁵ is cyclobutyl, cyclopropyl,methyl, cyclopropylmethyl, 1H-pyrazol-4-ylethyl, 2,2-dimethylpropyl,tetrahydro-2H-pyran-4-yl, spiro[3.3]heptan-2-yl,tetrahydro-2H-pyran-4-yl, cyclohexyl, tetrahydro-2H-pyran-3-yl,cyclopentyl, cyclohexylmethyl, butyl,4,5,6,7-tetrahydro-1H-indazol-5-yl, tetrahydrofuran-3-yl, or propyl,each of which is optionally substituted with 1, 2 or 3 R^(b)substituents.
 13. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R^(b) isindependently selected from halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, CN, OH, NH₂, OR^(c), C(O)R^(c), C(O)NR^(c)R^(c),C(O)OR^(c), OC(O)R^(c), and OC(O)NR^(c)R^(c); wherein the C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and C₆₋₁₀ aryl of R^(b) are eachoptionally substituted with 1, 2, or 3 independently selected R^(d)substituents.
 14. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R^(b) isindependently selected from halo, C₁₋₆ alkyl, C₆₋₁₀ aryl, CN, OH, NH₂,OR^(c), and C(O)NR^(c)R^(c), C(O)OR^(c); wherein the C₁₋₄ alkyl andC₆₋₁₀ aryl of R^(b) are each optionally substituted with 1, 2, or 3independently selected R^(d) substituents.
 15. The compound of claim 1,or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinR^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo,CN, NH₂, and OR^(e), wherein the C₁₋₄ alkyl of R^(d) are each optionallysubstituted with 1, 2 or 3 independently selected R^(f) substituents.16. The compound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R^(d) is independently selected from halo,CN, and OR^(e).
 17. The compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R^(c) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynylof RC are each optionally substituted with 1, 2, 3, 4, or 5 R^(f)substituents independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, and CN.
 18. The compound of claim 1,or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinRC is independently selected from H and C₁₋₆ alkyl.
 19. The compound ofclaim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein R⁶ is independently selected from H, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, CN, andORE, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl of R⁶ areeach optionally substituted with 1, 2, 3, or 4 R^(b) substituents. 20.The compound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R⁶ is H, halo, C₁₋₆ alkyl or C₁₋₆ alkoxy.21. The compound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein R⁶ is H.
 22. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein thesubscript m is 1 or
 2. 23. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R²,R³ and R⁶ are each H.
 24. The compound of claim 1, wherein the compoundis selected from:242,3-dihydro-1,4-benzodioxin-6-yl)-6-{4-[(cis-3-hydroxycyclobutyl)amino]piperidin-1-yl}benzonitrile;2-(4-(cyclopropylamino)piperidin-1-yl)-6-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)benzonitrile; 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-(4-(dimethylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-((1-(hydroxymethyl)cyclopropyl)methylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(2-(1-methyl-1H-pyrazol-4-yl)ethylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(3-hydroxy-2,2-dimethylpropylamino)piperidin-1-yl)benzonitrile;2-(2, 3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(tetrahydro-2H-pyran-4-ylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(cis-3-(hydroxymethyl)cyclobutylamino)piperidin-1-yl)benzonitrile;2-(2, 3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(trans-3-(hydroxymethyl)-4-methylpyrrolidin-1-yl)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo[b] [1,4] dioxin-6-yl)-6-(4-(spiro[3 0.3]heptan-2-ylamino)piperidin-1-yl)benzonitrile; 2-(2, 3-dihydrobenzo [b][1,4]dioxin-6-yl)-6-(4-((4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)methylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(trans-2-(hydroxymethyl)cyclohexylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(trans-3-methoxycyclobutylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(cis-3-methoxycyclobutylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)-6-(4-(3-(2-hydroxyethyl)pyrrolidin-1-yl)piperidin-1-yl)benzonitrile; 2-(2, 3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-(tetrahydro-2H-pyran-3-ylamino)piperidin-1-yl)benzonitrile;2-(2,3-dihydrobenzo[b] [1,4] dioxin-6-yl)-6-(4-(cis-2-(hydroxymethyl)cyclopentyl amino)piperidin- 1-yl)benzonitrile;2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-(trans-3-hydroxycyclobutylamino)piperidin-1-yl)benzonitrile;242,3-dihydro-1,4-benzodioxin-6-yl)-644-({[cis-2-hydroxycyclohexyl]methyl}amino)piperidin- 1-yl]benzonitrile; 2-(4-(cyclohexylamino)piperidin-1-yl)-6-(2,3-dihydrobenzo[b] [1,4] dioxin-6-yl)benzonitrile;2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-(3-(1-hydroxyethyl)pyrrolidin-1-yl)piperidin-1-yl)benzonitrile; 2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-(1-methylcyclopropylamino)piperidin-1-yl)benzonitrile2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-(trans-3-(hydroxymethyl)cyclobutylamino)piperidin-1-yl)benzonitrile 2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-(trans-4-hydroxycyclohexylamino)piperidin-1-yl)benzonitrile 2-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)-6-(4-(3-(hydroxymethyl)pyrrolidin-1-yl)piperidin-1-yl)benzonitrile;(1-((1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)methyl)cyclopropyl)methanol;1-(4-isopropylpiperazin-1-yl)-2-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)ethanone;trans-3-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclobutanol;cis-3-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclobutanol;trans-4-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclohexanol;N-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-1-(2-methylbiphenyl-3-yl)piperidin-4-amine;1-(2-methylbiphenyl-3-yl)-4-(pyrrolidin- 1-yl)piperidine;cis-4-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclohexanol;(cis-2-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclopentyl)methanol;(R)-2-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)butan-1-ol;N-cyclopropyl-1-(2-methylbiphenyl-3-yl)piperidin-4-amine;N-cyclopentyl-1-(2-methylbiphenyl-3-yl)piperidin-4-amine;1-methyl-5-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylicacid;2-(4-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclohexyl)acetonitrile;4-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclohexanecarbonitrile;4-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclohexanecarboxylicacid;1-(2-methylbiphenyl-3-yl)-N-(tetrahydrofuran-3-yl)piperidin-4-amine;(3-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclobutyl)methanol;N-(1-methoxypropan-2-yl)-1-(2-methylbiphenyl-3-yl)piperidin-4-amine;3-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclobutanecarboxylicacid;3-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclohexanecarboxylicacid;1-(4-chlorophenyl)-4-(1-(2-methylbiphenyl-3-yl)piperidin-4-ylamino)cyclohexanecarboxylicacid;3′-methoxy-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)biphenyl-2-carbonitrile;3′-fluoro-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)biphenyl-2-carbonitrile;2-cyclohexenyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzonitrile; and2-cyclohexyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzonitrile; or apharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, and a pharmaceuticallyacceptable carrier or excipient.
 26. A method of inhibiting PD-1/PD-L1interaction, said method comprising administering to an individual acompound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof.
 27. A method of treating a disease or disorderassociated with inhibition of PD-1/PD-L1 interaction, said methodcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt or a stereoisomer thereof.
 28. The method of claim 27,wherein the disease or disorder is a viral infection or cancer.
 29. Amethod of enhancing, stimulating and/or increasing the immune responsein a patient, said method comprising administering to the patient inneed thereof a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt or a stereoisomer thereof.